Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by late diagnosis, early metastasis, and resistance to conventional therapies. A major barrier to effective treatment is its desmoplastic and immunosuppressive tumor microenvironment, which restricts T-cell infiltration and dampens responses to immune checkpoint inhibitors (ICI). These features highlight the urgent need for innovative immunotherapeutic strategies capable of overcoming PDAC's immunologic and physical barriers. Chimeric antigen receptor (CAR)-macrophage (CAR-M) therapy has emerged as a promising approach to address these challenges. Unlike CAR-T or CAR-NK cells, CAR-Ms can efficiently infiltrate tumors, remodel the tumor microenvironment, phagocytose tumor cells, and stimulate adaptive immunity. This review highlights recent advances in CAR-M therapy for solid tumors, with an emphasis on PDAC. Preclinical studies show that CAR-Ms enhance antigen presentation, secrete proinflammatory cytokines, and recruit cytotoxic T cells, thereby amplifying antitumor responses. Progress in CAR-M engineering-such as dual-targeting strategies, CRISPR-based modifications, and combinations with ICIs or other therapies-further strengthens their therapeutic potential. Importantly, early-phase clinical trials in solid tumors support the safety, tolerability, and tumor-modulating capacity of CAR-Ms, laying the groundwork for their application in PDAC. To fully harness CAR-M therapy in PDAC, several challenges must be addressed, including improving CAR-M persistence and efficacy, optimizing tumor-specific targeting, developing scalable and cost-effective manufacturing platforms, and integrating strategic combinations with other therapies, such as ICIs and KRAS inhibitors. With continued innovation and clinical validation, CAR-M therapy has the potential to transform PDAC treatment, fulfill critical unmet clinical needs, and provide new hope for patients.